One of the essential requirements in the topical application of therapeutically active proteins is their stability in the pharmaceutical formulation. The stability must be ensured for a sufficiently long period of time both during storage under refrigeration and at ambient temperature and also at body temperature, as well as "in situ" for several hours. Thus far, no entirely satisfactory solutions have been found to meet these requirements. Various substances for stabilizing interferons have already been proposed. For example, hydroxyethylcellulose has been used as a carrier substance for the preparation of gels or ointments containing interferon. However, under the conditions of use, there was some loss of activity of the interferons which could only be reduced by the addition of a protease inhibitor (EP-A-142345).
For the stabilizing of interferons in gels, ointments, etc., it has also been proposed to use various sugar alcohols, optionally together with sugar acids or the salts thereof, mild reducing agents, anionic surfactant or combinations of these substances (EP-A-80879).
For stabilizing proteins and polypeptides such as interferons, more particularly IFN-gamma, in parenteral preparations, it has been proposed to use a physically and chemically modified gelatin, particularly as a replacement for human serum albumin (EP-A-162332).
Japanese Published Patent Application JP-A-61-277633 discloses the stabilizing of interferons in solution with certain surface-active substances.
EP-A-135171 mentions human serum albumin as a suitable stabilizer for oil/water microemulsions.
For the topical application of the synergistic combination IFN-beta/9-(1,3-dihydroxy-2-propoxy-methylguanine (DHPG) in the form of an ointment, according to U.S. Pat. No. 4,606,917, albumin, dextrose and buffer substances are proposed as stabilizers.
A stabilizing effect to the standard required has not yet been achieved with the substances proposed thus far for stabilizing therapeutically active proteins, particularly in hydrogels.
The aim of this invention was to provide a stabilizer for therapeutically active proteins in pharmaceutical preparations for topical use, particularly in hydrogels, which in addition to being physiologically acceptable, satisfies all the requirements imposed on formulations of this kind, especially with respect to the optimum availability of the active substance and the full development of its activity and with respect to the gentlest possible method of preparation which takes account of the vulnerability of the proteins to shear forces.
Various substances have been investigated with respect to their suitability for solving the above-described problem. It was found, surprisingly, that even small amounts of hydrophobic substances used as additives in very finely divided form, particularly paraffin oils, have a stabilizing effect on various therapeutically active proteins which is superior to the effect of the substances proposed up till now. This result is all the more surprising as the pharmaceutical preparations for topical use which belong to the prior art, such as ointments in which hydrophobic substances are used as carriers in a suitably large proportion, require the separate addition of a stabilizer.